Adoptive T cell therapy (ACT) can lead to impressive results but the frequency of success is low. Generally success correlates with persistence ofthe adoptively transferred T cells. Our results indicate that repetitive TCR stimulation, which occurs during ACT leads to activation induced cell death (AICD) of CDS effector cells. Thus AICD may contribute to poor persistence of adoptively transferred T cells. Recently, it has become possible to genetically modify autologous T cells by transduction with a tumor-specific TCR such as the high affinity TIL13S3i TCR central to this application. While little is known about the biology of these genetically modified cells, we show that they also undergo AICD, Thus a feasible translational approach to enhance persistence of genetically modified T cells will be to insert an additional protective gene into the vector expressing the TlL1383i TCR. Therefore, it will be necessary to understand the signal transduction pathways leading to AICD. Our preliminary data identify JNK, p53, and AIF as mediators of AICD in T cells expressing a native TCR. However, similarities and differences between T cells expressing a native vs. a transduced TCR as well as downstream mediators and remain to be elucidated. We will therefore compare AICD and anti-tumor efficacy between T cells natively expressing the TlL1383i (derived from the h3T transgenic model) and T cells that have been transduced with the TlL31S3i TCR. We observed that ROS generation is a common phenomenon associated with AICD and that pharmacological inhibition with ROS scavenger results in protection from cell death without interfering with T cell activation, which places redox regulation at a central point for therapeutic intervention. It is our hypothesis is that genetically enhancing the antioxidant capacity of TIL1383i TCR transduced T cells will lead to specific and sustained protection from AICD thereby increasing persistence, memory pool development and anti-tumor efficacy following adoptive T cell transfer Our aims are: Specific Aim 1. To dissect the mechanism of AICD in TCR transduced T cells after repetitive TCR stimulation. Specific Aim 2. To determine how increasing the antioxidant capacity of TCR transduced T cells impacts, survival, function, and memory development in vitro. Specific Aim 3. To evaluate how increased antioxidant capacity of adoptively transferred TCR transduced T cells affects their persistence and memory development as well as tumor regression in vivo. Our approach could directly impact ongoing clinical trials, in which genetically modified T cells are used for immunotherapy of melanoma.